Infection of the airways is a major cause of death worldwide and a persistent problem in critical care medicine. Mortality from airway infection is on the rise and thus there is an urgent need to develop alternative treatments. Innate response activator (IRA) B cells are a unique B cell population we recently discovered that protects against microbial sepsis. In a mouse abdominal sepsis model, peritoneal B1a B cells recognize bacteria with pattern recognition receptors, migrate to the spleen, differentiate to IRA B cells, and protect against overwhelming infection by mechanisms that involve the cytokine and growth factor GM-CS. IRA B cells, which we also identified in humans, are vital to how the host clears bacteria. We have now shown in preliminary experiments that B1a B cells and IRA B cells also reside in the pleural cavity. Mice lacking IRA B cells rapidly succumb to bacterial airway infection, fail to accumulate IgM-producing cells in the lungs, and fail to generate secretory IgM. Moreover, the pleural cavity is the source of IgMhigh B cells that accumulate in the lungs, whereas injection of pleural cavity IRA B cell precursors to the pleura of IRA B cell knockouts restores IgM responses and protects against bacterial infection. Here we will test the hypothesis that pleural cavity-derived IRA B cells control the generation and accumulation of natural antibody producing cells in the lung. IRA B cells, we propose, are essential coordinators of immune defense and protect against airway infection. The project is important because it is based on a strong phenotype and has clear translational potential and it is innovative because it explores the biology of a newly- discovered cell, identifies a previously unknown GM-CSF-IgM axis, and identifies the pleural cavity as an important hub for immune cells.